Oral mucositis (OM) is a common, devastating complication of radiation and chemotherapeutic antineoplastic regimens, particularly in patients with head and neck cancers, for which no effective therapy is currently available. We have identified a 21 amino acid peptide derived from a novel 18-kD Antrum Mucosal Protein (AMP-18) that facilitates healing of injured oral mucosal tissue in two animal models, and increases the efficacy of cisplatin and radiation treatment. Subcutaneous administration of the AMP peptide protected the surface epithelium of mouse tongue against acute radiation injury. Treatment with the peptide also delayed the appearance and reduced the extent of ulcer formation in the buccal mucosa of hamsters exposed to radiation alone, or with cisplatin. AMP-18 functions as a pleiotropic agent in cultured cells and in vivo, exhibits anti- apoptotic, motogenic and mitogenic effects, and protects epithelial barrier function and structure by targeting tight junction proteins. To determine the mechanisms by which AMP-18 and the peptide exerts their effects, we recently identified the cholecystokinin-B/gastrin receptor (CCKBR) as a receptor for AMP-18, and verified its expression in normal human oral mucosal tissue by immunohistochemistry. Binding of AMP-18 to CCKBR activates MAPKs, Rho, Akt and PKC? pathways. The AMP peptide exhibits the same biological functions as does the full-length protein. To find out if treatment of OM with AMP peptide could block the tumorolytic effect of radiation, we created a xenograft model of human cancer cells in nude rats that received radiation with or without AMP peptide. Administration of AMP peptide unexpectedly enhanced radiation-induced growth inhibition without causing any adverse effects in the animals. This tumor suppressor function is supported by observations showing that expression of AMP-18 is downregulated or absent in gastric cancer tissue, and that transfection and overexpression of AMP-18 in gastric cancer cell lines can induce apoptosis or senescence. To develop AMP peptide as a therapeutic agent, we investigated the effects of the peptide on growth of a head and neck cancer cell line, SCC61, in the presence of cisplatin. Treatment with AMP peptide or recombinant human (rh) AMP-18, together with cisplatin, additively reduced cell growth. Thus AMP peptide/rhAMP-18 has dual effects in vitro and in vivo: it protects and facilitates healing of injured oral mucosal tissue, and enhances efficacy of antineoplastic strategies. Specific Aim #1 is to demonstrate in an orthotopic mouse model of squamous cell cancer of the oral tongue, that AMP peptide administered together with radiation exerts both its radioprotective and tumor-suppressing properties in the same animal. Aim #2 is to identify mechanisms by which AMP peptide heals injured oral mucosal tissue, but can also inhibit growth of head and neck cancer cells following exposure to radiation and/or cisplatin. Identification of molecular mechanisms by which AMP peptide exerts its pleiotropic effects could speed its development as a novel therapeutic for OM in patients with head and neck cancers.